ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.719-2A>C

dbSNP: rs1952654925
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001319561 SCV001510309 uncertain significance Retinoblastoma 2022-07-12 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1020043). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the RB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365).
Ambry Genetics RCV004034979 SCV005034605 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-12 criteria provided, single submitter clinical testing The c.719-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 8 in the RB1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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